9alpha-halo-11-hydroxy testosterone and intermediates in the production thereof



United States Patent 9a-HALO-l1-HYDROXY TESTOF IERUNE AND IN- TERMEDIATES IN THE PRODUCTIGN THEREOF Albert Wettstein and Georg Anner, Basel, and Charles Meystre, Arleshcim, Switzerland, assignors to Cilia Corporation, a corporation of Delaware No Drawing. Filed May 18, 1955, Ser. No. 509,392

Claims priority, application Switzerland May 26, 1954 12 Claims. (Cl. 260-23955) This invention relates to A -3-oxo-11,17-dihydroxy- 17-R-9-halogeno-androstenes and esters and ethers, for example acetals, thereof, wherein R stands for hydrogen or a lower alkyl group, for example, methyl, and wherein halogeno stands, for example, for bromine, chlorine, fluorine and iodine. Especially valuable are the aforesaid compounds where halogeno is chlorine and fluorine, for example, A 3 oxo 11,8,17/8-dihydroxy-9a-chloroandrostene, A 3 oxo-l15,17fl-dihydroxy-9a-fluoro-androstene, A 3 oxo 11,8,17 3-dihydroxy-17a-methy1-9mchloro-androstene, A 3 oxo-l15,17fi-dihydroxy-l7amethyl-9a-fluoro-androstene and the esters thereof, for example, the 17,8 esters with carboxylic acids, e.g. pro piomc acid, cyclopentylpropionic acid, and the like.

The novel compounds of the present invention demonstrate valuable physiological activity. They possess the activity of testosterone and can be employed in the same way to treat the same conditions as is testosterone. The novel compounds in which the halogeno radical is bromine are readily prepared by converting 41 3-oxo-17-hydroxy-17-R-androstadiene, preferably in the form of the 17-ester thereof, more particularly A 3-oxo-17-acyloxy-17-R-androstadiene, into A -3-oxo-11B- hydroxy-l7-acyloxy-17-R-9a-bromo-androstene, for example, by treating the former with N-bromoacetamide or N-bromosuccinimide, preferably in the presence of a catalyst, such as sulfuric acid. The resulting A -3-oxo- -1 1 ,B-hydroxy-l7-acyloxy-17-R-9a-bromo-androstene can then be converted into A -3-oxo-11,8-hydroxy-17-acyloxy-17-R-9oc-chloro-androstene and the corresponding 90c-flL1010 compounds in the following manner:

The A -3-ox0-1lfl-hydroxy-l7-acyloxy-17-R-9a-bromoandrostene is treated with a dehydrobrominating agent, that is, an agent which splits off hydrogen bromide, to form A -3-oxo-17/3-acyloxy-l7-R-9,1 lfi-oxido-androstene which is then treated with hydrogen chloride to produce A 3-oxo-11,8-hydroxy-17-acyloxy-17-R-9a-chloro-androstene or with hydrogen fluoride to produce A -3-oxo-11B- hydroxy 17 acyloxy-l7-R-9u-fluoro-androstene. When hydrogen iodide is employed there is obtained A -3-0xo- 1 l3-hydroxy-17-acyloxy-17-R-9ot-iodo-androstene.

As dehydrobrominating agents there can be employed advantageously hydroxides or oxides of metals of the first and second groups of the periodic system, for example, silver oxide, and also tertiary bases such as pyridine or collidine, or aluminum oxide. It is of advantage to use a tertiary base together with one of the aforesaid monovalent or divalent metal hydroxides or oxides.

The A -3-oxo-17-hydroxy-17-R-androstadiene and their esters employed as starting compounds, can be prepared by known methods, for example, by splitting off water from A -3-oxo-11,17-dihydroxy-17-R-androstene or their 17-esters, for example by treating A -3-oxo-11- hydroxy-17-acyloxy-17-R-androstene with phosphorus oxychloride and pyridine.

R in the above named compounds stands for hydrogen or a lower alkyl group, e.g., methyl.

The novel compounds comprising the invention can be employed in combination with any suitable carrier to facilitate the administration thereof.

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The following examples will serve to illustrate the invention:

Example 1 A solution of milligrams of A -3-oxo-17/3- propionyloxy-androstadiene in 4.5 cc. of tertiary butanol and 1 cc. of water is mixed, while stirring, at about 15 C. with milligrams of N-bromoacetamide and 1 cc. of sulfuric acid of 4 percent strength. After a few minutes the reaction solution becomes yellow-brown. For the purpose of decolorization an aqueous 1 percent solution of sodium sulfite is then added. 50 cc. of water are added, the mixture is extracted with a mixture of chloroform and ether (1:3), and the extract is washed with ice-cold dilute 1 percent sodium carbonate solution and water. By evaporating the dried chloroform-ether solution in vacuo there is obtained A -3-oxo- 1 lfi-hydroxy-17B-propionyloxy-9a-bromo-androstene (9abromo- 1 1 fi-hydroxy-testosterone propionate) A solution of 100 milligrams of the above A -3-oxo- 11,8 hydroxy-17fl-propionyloxy-9a-bromo androstene in 2 cc. of anhydrous pyridine is agitated in the dark for 24 hours with milligrams of freshly precipitated and dried silver oxide. Silver oxide is then filtered off with suction, and the filtrate is evaporated in vacuo. The residue consists of A -3-oxo-176-propionyloxy-9,11,8- oxido-androstene and A -3-oxo-175-hydroxy-9Jlfl-oxidoandrostene, which can be separated by chromatography with the aid of aluminum oxide.

50 milligrams of A -3-oxo-17,6-propionyloxy-9,115- oxido-androstene dissolved in 5 cc. of dioxane, are mixed with 1.2 cc. of 2.5 N-hydrochloric acid, and the Whole is allowed to stand for one hour at room temperature. Water is then added, and the mixture is extracted with a mixture of chloroform and ether (1:3). After washing the extract with water, drying it and evaporating the solvent in vacuo, there is obtained A -3-oxo-11B-hydroxy- 17fl-propionyloxy-9lx-chloro-androstene.

By reacting the above 9,11fi-oxido-compound with hydrofluoric acid there is obtained A -3-oxo-115-hydroxy- 17,8-propionyloxy 9a-fluoro-androstene.

In an analogous manner, for example, A -3-oxo- -cyclopentyl propionyloxy-androstadiene can be converted into A -3-oxo-1lfl-hydroxy-17,8-cyclopentylpropionyloxy-9a-chloro-androstene and A -3-oxo-1lB-hydroxy-l7,8-cyclopentylpropionyloxy-9a-fluoro-androstene.

Example 2 A solution of 200 milligrams of A -3-oxo-17fi3 hydroxy-l7oc-methyl-androstadiene in 10 cc. of tertiary butanol and 2 cc. of water are mixed, while stirring, at about 15 C. with 250 milligrams of N-bromacetamide and 2 cc. of sulfuric acid of 4 percent strength. The further procedure is analogous to that described in Example 1. The resulting A -3-oxo-115,17fi-dihydroxy- 17ot-methyl-9a-bromo-androstene can be converted by the process described in Example 1 by way of A -3-oxo-17B- hydroxy-17a-methyl-9,1lfl-oxido-androstene into A -3-oxo 1 1B,l7/3-dihydroxy-17lx-methyl-9ot-chloro-androstene and A 3 oxo 115,175 dihydroxy 1704 methyl 9afluoro-androstene.

The aforesaid A -3-oxo-11,17-dihydroxy-17-R-9-halogeno-androstenes can be esterified, particularly in the 17-position to produce the corresponding 17-acyloxy compounds. For this purpose the customary reagents may be used, for example, carboxylic acid chlorides or carboxylic acid anhydrides or isopropenyl acylates, if desired, in approximately equivalent proportions. Thus, for example, the radicals of carboxylic acids containing up to and including eleven carbon atoms, e.g. acetic acid, trimethyl acetic acid, propionic acid, Valerie acid, oenanthio acid, undecylenic acid, benzoic acid, phenylpropionic 3 acid, cyclopentylpropionic acid, or of polycarboxylic acids, hydroxy-carboxylic acids, polyoXy-methylene-carboxylic acids, or inorganic acids, may be introduced to produce the corresponding 17-acyloxy compounds.

What is claimed is:

1. A 3 oXo-9u-halo-11fi-hydroxy-17/3-OR-17oz-R androstene, in which R is a member selected from the group consisting of hydrogen and acyl derived from a carboxylic acid having one to eleven carbon atoms and R is selected from the group consisting of hydrogen and lower alkyl.

2. A -3-oXo-1 1e, l7-dihydroxy-9a-chloro-androstene.

3. A -3-oxo-1 1/3,17-dihydroxy-9oc-fluoro-androstene.

4. A 3 oxo 11 3 hydroxy-l7B-propiony1oxy-9achloro-androstene.

5. A 3 x0 11,6 hydroxy-l7/8-propi0nyloxy-9afluoro-androstene.

6. A 3 oxo 11/3 hydroXy 176 cyclopentylpropionyloxy-9a-chloro-androstene.

7. A 3 oxo 115,175 dihydroXy-17a-methyl-9otchloro-androstene.

8. A 3 oxo 1113,1713 dihydr0xy-17a-methyl-9afiuoro-androstene.

9. 9ot-halo-1lfi-hydroxytestosterone of the formula wherein X is a halogen and R is a member selected 4 10. 9a-halo-11/3-hydroxy-17a-lower alkyl testosterone of the formula wherein X is a halogen and R is a lower alkyl radical. 11. 9,1lfl-epoxy-17-alkyltestosterones represented by the following formula References Cited in the file of this patent UNITED STATES PATENTS Reichstein Oct. 22, 1946 Farrar Apr. 26, 1955 OTHER REFERENCES Cohn et al., Chem. and Ind. 1951. Fried, Jour. Am. Chem. Soc. 75, 2273 (1953); Jour.

from the group consisting of hydrogen and lower alkanoyl. 40 Am. Chem. Soc. 76, 14556 (1954). 

11. 9,11B-EPOXY-17-ALKYLTESTOSTERONES REPRESENTED BY THE FOLLOWING FORMULA 